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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
initiated February 2003 - end date unknown
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Principles of method if other than guideline:
A one year study of dehydroepiandrosterone (DHEA) was conducted in male and female Cynomolgus monkeys in support of a New Drug Application (NDA) of DHEA submitted to the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe dyspareunia in menopausal women. DHEA suspended in 0.4% aqueous methylcellulose was administered daily to male and female monkeys by nasogastric intubation at doses of 0, 2 and 10 mg/kg/day (4/sex/group). An additional group received 10 mg/kg DHEA and 0.3 mg/kg estradiol, while another group received 10 mg/kg DHEA, 0.3 mg/kg estradiol and a selective estrogen modulator (EM 652 HCl; SCH 57068 HCl; Acolbifene). Observations included mortality, clinical signs, body weights, food consumption, ophthalmoscopy, hematology, clinical chemistry, urinalysis, gross pathology, organ weights and histopathology.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Prasterone
EC Number:
200-175-5
EC Name:
Prasterone
Cas Number:
53-43-0
Molecular formula:
C19H28O2
IUPAC Name:
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one
Test material form:
solid
Details on test material:
white solid
Specific details on test material used for the study:
IDENTITY: Dehydroepiandrosterone (DHEA); EM-760
- Lot: EM-760-13
- CAS Registry Number: 53-43-0
- Generic Name: Prasterone
- Molecular Weight: 288.4

SOURCE OF TEST MATERIAL
- Source of test material: no data
- Purity: 99.7%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Not specified
- Stability of the test substance in the solvent/vehicle: Not specified

FORM AS APPLIED IN THE TEST
- Suspension

Test animals

Species:
monkey
Strain:
other: Cynomolgus
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not specified
- Age: Young adult, males 4-6 years, females 6-18 years.
- Weight: 2.9 to 7.1 kg
- Housing: Not specified
- Diet: Not specified
- Water: Not specified

ENVIRONMENTAL CONDITIONS
- Temperature: Not specified
- Humidity (%): Not specified
- Photoperiod (hrs dark / hrs light): Not specified

Administration / exposure

Route of administration:
other: Nasogastric intubation
Details on route of administration:
Method: Oral by nasogastric intubation.
Frequency: The test substance was administered once daily
Vehicle:
methylcellulose
Remarks:
0.4% aqueous
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- DHEA was prepared as a suspension in 0.4% aqueous methylcellulose.

VEHICLE
- Concentration DHEA in vehicle: 0 mg/mL (group 1); 1 mg/mL (group 2); 5 mg/mL (group 3); 5 mg/mL (group 4); 5 mg/mL (group 5)
- Amount of vehicle (if gavage): 2 mL/kg body weight
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1 year
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1 (vehicle control)
Dose / conc.:
2 mg/kg bw/day (actual dose received)
Remarks:
Group 2 (DHEA low dose)
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Group 3 (DHEA high dose)
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Group 4 (DHEA high dose and 0.3 mg/kg estradiol)
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Group 5 (DHEA high dose, 0.3 mg/kg estradiol and 40 mg/kg EM-652-HCl)
No. of animals per sex per dose:
4 animals/sex/group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
- In-life observations included mortality, clinical signs, body weights, food consumption, ophthalmoscopy, and urinalysis. Schedule and frequency of observations were not specified.
- Observations included hematology and clinical chemistry. Blood was collected on days 1, 184 and 359
Sacrifice and pathology:
- Observations included gross pathology, organ weights and histopathology.

ORGAN WEIGHTS
- Female monkeys: Organ weights were conducted on the following tissues: Adrenals, ovaries, pituitary, thyroid/parathyroids, uterus, vagina.
- Male monkeys: Organ weights were conducted on the following tissues: Adrenals, epididymides, pituitary, prostate, seminal vesicles, testes, thyroid/parathyroids.

HISTOPATHOLOGY
- Female Rats: Histopathologic examinations were conducted on the following tissues: Mammary gland, ovary, oviduct, pituitary, uterus, vagina.
- Male Rats: Histopathologic examinations were conducted on the following tissues: epididymis, mammary gland, pituitary, prostate, seminal vesicle, skin/subcutis (dorsal), spleen, testis, thymus.
Other examinations:
- Toxicokinetics parameters (Days 1, 184 and 359): AUC(0-24 hr) in ng*hr/mL for DHEA and DHEA sulfate
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
- No signs with DHEA alone.
- Estrogen related signs were observed in monkeys receiving both DHEA and estradiol.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight decrease observed with estradiol and DHEA.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No adverse effects
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- No drug related changes were observed in females.
- Only changes were observed in males that received estradiol with DHEA.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No changes with DHEA alone.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No changes
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymis, testis, spleen and thymus in males) all attributed to estrogenic effects.
- Thyroid weight was also increased. This was presumably the result of estrogenic stimulation of SHBG and possible TBG resulting in reduced feedback and increased TSH.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No DHEA only effects
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No changes with DHEA alone.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Assumes that the effects on endocrine organ weights are pharmacologic.

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Toxicokinetics:

Female monkeys given 2 and 10 mg/kg DHEA orally for 184 days had serum AUC's0-24h of 281 and 418 ng.h/ml and males had AUC's of 392 and 684 ng.h/ml. Women given 0.5% (6.5mg) DHEA intravaginally for 7 days had a mean serum AUC0 -24h of 56 ng.h/ml. Exposur margins are 5 and 7x for females and 7 and 12x for males.

Applicant's summary and conclusion

Conclusions:
In a one year monkey oral toxicology study, DHEA produced no adverse effects in male and female monkeys up to 10 mg/kg/day. Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymis, testis, spleen and thymus in males) were attributed to estrogenic/androgenic effects that were assumed to be pharmacologic in nature. A NOAEL of 10 mg/kg was identified for male and female monkeys.